Vitamin A deficiency has been associated with increased risk or susceptibility to carcinogenesis, and natural and synthetic vitamin A derivatives (retinoids) have been shown to inhibit skin tumor promotion and to cause regression of existing skin tumors. The food and fragrance additive citral inhibits some of the biological activities of retinol in the epidermis. Metabolic studies suggest that this is due to inhibition by citral of the metabolic oxidation of retinol to retinoic acid. Based on these observations the hypothesis is proposed that retinoic acid formation in the epidermis is a crucial metabolic step in the prevention of carcinogenesis. Consequently, agents that modulate this process could increase the risk for carcinogenesis, even though they are not carcinogens or mutagens per se. To test this hypothesis a series of biochemical, metabolic, and tumor promotion experiments is proposed in hairless mice. The amounts of ornithine decarboxylase activity, a possible marker for tumor promotion, induced by the tumor promoter tetradecanoylphorbol- 13-acetate will be measured in the epidermis of mice at different stages of vitamin A deficiency. The ability of citral to modulate tumor promotion will be tested in a two stage skin carcinogenesis protocol. The specificity of the metabolic impact of citral on retinol metabolism will be determined in a series of detailed studies of retinoid metabolism in the skin.